The long-term goal of this project is to discern the mechanism(s) by which loss of renal parenchyma causes progressive glomerular scarring. This process is relevant to human renal disease because glomerular sclerosis is a marker for irreversible damage, and clinical studies suggest that when it involves a critical number of glomeruli, progressive scarring occurs in the remainder regardless of the nature of the initial injury. The problem will be addressed in the remnant kidney (RK) model because it develops progressive glomerular sclerosis, the pathogenesis of the glomerular lesion is not complicated by continuing or residual effects of the initiating agent, it appears to share the pathophysiology of reduced nephron mass observed in humans, and the physiological abnormalities are amenable to dietary and pharmacologic manipulations. We will define the extent and nature of glomerular sclerosis in the RK model using morphological methods and a biochemical determination of collagen, and the development of glomerular lesions will be correlated with the selectivity of proteinuria. The relationship of decreased autoregulatory efficiency to glomerular epithelial cell and mesangial function will be determined, and we will test to see if rats with a congenital predisposition to develop glomerular sclerosis and a model of massive proteinuria caused by a transplantable pituitary tumor have the same defects in autoregulatory efficiency and functional abnormalities. The central hypothesis that we wish to test is whether morphologically intact, normally functioning glomerular cells are not only necessary for glomerular function but whether GEC and/or mesangial dysfunction is involved in the pathogenesis of glomerular injury and scar formation. Specifically, in the RK model, we propose to distinguish between barotrauma which injuries glomerular structures and leads directly to cell generation and scarring and subtle injury to the cellular elements in the glomerulus which progress to glomerular sclerosis by virtue of dysfunction of the cells which are no longer able to maintain the integrity of the glomerular capillary wall.